The functional syncytium comprising osteocytes, osteoblastic cells, marrow stromal cells, and endothelial cells of the blood vessels is thought to be the mechanosensory apparatus by which bone, as an organ, detects the need for mechanical adaptation and microdamage repair and initiates the appropriate adaptive responses. Consistent with this, studies leading to this project have revealed that the increased bone fragility that results from glucocorticoid excess in mice and humans is associated with increased bone fragility that results from glucocorticoid excess in mice and humans is associated with increased osteocyte apoptosis. Conversely, bisphosphonates and intermittent PTH, two treatments that are effective in steroid-induced osteoporosis (as well as estrogens, androgens, and calcitonin) prevent osteocyte and osteoblast apoptosis in vitro and in vivo. In addition, it has been demonstrated in vitro than the anti-apoptotic effect of bisphosphonates and estrogens results from rapid activation of the extracellular signal-regulated kinases (ERKs) and that mechanical signals also cause ERK activation in osteocytic cells. Collectively, these lines of evidence give credence to the hypotheses that disruption of the osteocyte network by apoptosis, resulting from hormonal or strain changes, may contribute to microdamage accumulation and increased bone fragility; whereas prevention of osteocyte viability may increase bone strength. Hormonal, pharmacological, and mechanical signals converge on common signal transduction pathways that influence the viability of osteocytes and the integrity of the lacuno-canalicular network, to orchestrate the appropriate addition or removal of bone and participate in the detection and repair of fatigue microdamage. To advance this hypothesis, the effects of pro- and anti-apoptotic agents (glucocorticoids and bisphosphonates) as well as mechanical signals on focal adhesion molecules (FAK and Pyk2), MAP kinases, intracellular calcium, and connexin channels and hemichannels will be determined in vitro. Further, the contribution of osteocyte apoptosis to mechanical strength will be studied using a murine model of glucocorticoid excess treated with bisphosphonates. These studiers should chart the signaling pathways controlling osteocyte viability and advanced our understanding of the contribution of altered prevalence of osteocyte apoptosis to bone strength.